Human GRIA variants and neurological diseases: from molecular mechanism to rescue pharmacology

人类 GRIA 变异与神经系统疾病：从分子机制到救援药理学

基本信息

批准号：
10458777
负责人：
HONGJIE YUAN
金额：
$ 23.48万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10458777
关键词：
AMPA Receptors Acids Address Affect Agonist Behavior Biological Assay Brain Bulla Cell Surface Receptors Cell Survival Cells Clinical Communication Complementary DNA Complex Data Disease Economics Emotional Epilepsy Evaluation FDA approved Family Fluorescence Microscopy GRIA3 gene Genes Genetic Variation Glutamates Hippocampus (Brain)Human Individual Inherited Intellectual functioning disability Intervention Ion Channel Ion Channel Gating Knowledge Learning Ligands Location Luciferases Mammalian Cell Measures Mediating Memory Molecular Morphology Mutation Neurodevelopmental Disorder Neurodevelopmental Problem Neurologic Symptoms Neurons Patients Pattern Pharmaceutical Preparations Pharmacology Play Population Property Psyche structure Publishing RNA Splicing Reporting Role Running Schizophrenia Series Societies Surface Swelling Synapses Synaptic Transmission Testing Time Variant Vertebral column Xenopus oocyte antagonist autism spectrum disorder beta-Lactamase channel blockers clinically relevant disability exome sequencing experimental study extracellular gain of function genome-wide human disease inhibitor insight kainate loss of function nervous system disorder neuron development neuropsychiatric disorder neuropsychiatry neurotoxicity neurotransmission novel novel therapeutic intervention personalized medicine positive allosteric modulator prevent receptor receptor function response targeted treatment trafficking virtual

AMPA Receptors Acids Address Affect Agonist Behavior Biological Assay Brain Bulla Cell Surface Receptors Cell Survival Cells Clinical Communication Complementary DNA Complex Data Disease Economics Emotional Epilepsy Evaluation FDA approved Family Fluorescence Microscopy GRIA3 gene Genes Genetic Variation Glutamates Hippocampus (Brain)Human Individual Inherited Intellectual functioning disability Intervention Ion Channel Ion Channel Gating Knowledge Learning Ligands Location Luciferases Mammalian Cell Measures Mediating Memory Molecular Morphology Mutation Neurodevelopmental Disorder Neurodevelopmental Problem Neurologic Symptoms Neurons Patients Pattern Pharmaceutical Preparations Pharmacology Play Population Property Psyche structure Publishing RNA Splicing Reporting Role Running Schizophrenia Series Societies Surface Swelling Synapses Synaptic Transmission Testing Time Variant Vertebral column Xenopus oocyte antagonist autism spectrum disorder beta-Lactamase channel blockers clinically relevant disability exome sequencing experimental study extracellular gain of function genome-wide human disease inhibitor insight kainate loss of function nervous system disorder neuron development neuropsychiatric disorder neuropsychiatry neurotoxicity neurotransmission novel novel therapeutic intervention personalized medicine positive allosteric modulator prevent receptor receptor function response targeted treatment trafficking virtual

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项目摘要

Modified SUMMARY-ABSTRACT Neuropsychiatric disorders are associated with disabilities of brain function that affect individual’s behavior, memory and ability to learn. Such disabilities can carry devastating mental and economic consequences for the individuals, their families, and society. The molecular basis of a subset of these disabilities involves monogenic channelopathies, a term used to describe disease-causing variants in various ion channels. The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), ligand-gated ion channels, represent tetrameric complexes comprised of varying combinations of four subunits, GluA1-4 (encoded by GRIA1-4). AMPARs mediate the fast component of excitatory post-synaptic currents. Patterns of AMPAR activation can trigger a change in synaptic strength, which is widely considered to be a cellular correlate of learning and memory, and play an important role in neuronal development. Following the first report on a disease-causing AMPAR variant in 2007, a large number of human variants (>200) scattered across four AMPAR subunits have been identified in patients with various neurodevelopmental and neuropsychiatric problems, including autism and intellectual disability. It has been suggested that GRIA2 and GRIA3 genes have genome-wide significance for autism and schizophrenia, respectively. Despite the rapid advance in identification of new variants, there are neither virtually no systematic functional analyses for the variants nor any evaluation of possible treatment options for the patients. We propose a series of functional and pharmacological experiments that will fill this gap in our knowledge and will determine the mechanisms underlying the effects of 64 disease-associated GRIA2 and GRIA3 variants that do not exist in healthy population. The proposed experiments will explore how the receptor and neuronal function is impacted by genetic changes in AMPAR GRIA genes. The results of our pharmacological experiments assessing the effects of FDA-approved drugs on AMPARs with patient-specific variants will advance opportunities for personalized medicine by suggesting new therapeutic strategies for mitigation of functional changes by these variants. Our data will also provide novel functional insight into the AMPAR function. Aim 1. How do human GRIA variants impact receptor function? We assess the effect of 64 missense GRIA2 and GRIA3 variants on agonist potency, time course of current responses, and cell surface receptor trafficking. Aim 2. How do human GRIA variants influence neuronal function? We will assess neuronal synapse number, spine morphology, trafficking locations (synaptic vs extrasynaptic), spontaneous mEPSCs, and the ability of induced neurotoxicity (cell viability as well as dendritic swelling) by a set of GRIA2 and GRIA3 variants. Aim 3. How can AMPAR channelopathies best be treated? For the gain-of-function variants, we will measure the IC50 for competitive antagonists, negative allosteric modulators, or channel blockers (including FDA-approved). We will estimate the EC50 for positive modulators (e.g. ampakines) for the loss-of-function variants.

修改的摘要提取神经精神疾病与影响个人的行为，记忆和学习能力的脑功能障碍有关。这种疾病会对个人，家人和社会产生毁灭性的心理和经济后果。这些疾病子集的分子基础涉及单基因通道病，该术语用于描述各种离子通道中引起疾病的变体。 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPARS）（AMPARS），配体门控离子通道代表四个亚基组成的不同组合，由GLUA1-4（GLUA1-4编码）。 AMPAR介导兴奋性突触后电流的快速成分。 AMPAR激活的模式可以触发突触强度的变化，突触强度被普遍认为是学习和记忆的细胞相关性，并且在神经元发育中起着重要作用。在2007年关于引起疾病的AMPAR变体的第一个报告之后，在患有各种神经发育和神经精神疾病的患者中，已经确定了散布在四个AMPAR亚基中的大量人类变体（> 200），包括自闭症和智力残疾。已经提出，Gria2和Gria3基因分别对自闭症和精神分裂症具有全基因组意义。尽管鉴定新变体方面有迅速的进步，但几乎没有针对这些变体的系统功能分析，也没有对患者的可能治疗方案进行任何评估。我们提出了一系列功能性和药物实验，这些实验将填补我们的知识，并确定健康人群中不存在的64种与疾病相关的GRIA2和GRIA3变体的作用的机制。提出的实验将探讨接收器和神经元功能如何受到AMPAR GRIA基因的遗传变化的影响。我们的药物实验的结果评估了FDA批准的药物对具有患者特异性变异的AMPAR的影响，将通过提出新的治疗策略来促进这些变体来缓解功能变化的新型治疗策略。我们的数据还将为AMPAR功能提供新的功能洞察力。目标1。人Gria变体如何影响受体功能？我们评估了64个错义Gria2和Gria3变体对激动剂效力，当前反应的时间过程以及细胞表面受体运输的影响。目标2。人Gria变体如何影响神经元功能？我们将评估神经元突触数量，脊柱形态，运输位置（突触与促触觉），赞助MEPSC以及一组Gria2和Gria3变体的诱导神经毒性（细胞活力以及树突状吞咽）的能力。目标3。如何最好地治疗AMPAR通道病？对于功能障碍的变体，我们将测量竞争性拮抗剂，负变构调节器或通道阻滞剂（包括FDA批准）的IC50。我们将估算出正调节剂（例如两栖动物）的EC50，以供功能丧失变体。